Major Affective Disorders are highly prevalent illnesses in our society. More than 15% of the population will suffer major depressive episode in their lifetime and the incidence and therefore life-time prevalence is on the increase. Better medical treatment for individuals with these illnesses to ameliorate the symptoms has been developed, however the cost to society in terms of dollars and intangibles is great. In addition, up to 20% of the patients are refractive to treatment, while others have to deal with very unpleasant side-effects of the medication. The underlying cause of the illness is unknown. In the past twenty years progress has been made in the study of the genetic components of these illnesses. Epidemology studies of twin, adoption and family data have shown strong familial component in the Bipolar subtype of Affective Disorders. The Amish study has provided an excellent opportunity to investigate the underlying basis for familiar predisposition to bipolar affective disorder. Recently, we have demonstrated strong evidence for linkage of 11p markers, HRAS1 and insulin, to a gene predisposing members of one large Old Order Amish kindred to bipolar affective disorder. This finding provides an important challenge--to directly identify the gene responsible for predisposition to bipolar affective disorder in pedigree 110. The studies proposed in this application are focused on this goal. An intermediate step in this process is the generation of an increased number of polymorphic markers in the region of 11p which includes the bipolar I gene. The markers will then be used to provide increased genetic definition of the chromosomal segment which includes the gene. Subsequent work will then be directed towards the isolation of a complete set of DNA clones spanning this region. To accomplish this objective, I propose to utilize the recently developed yeast artificial chromosome vectors. Towards the end of the granting period I will attempt to identify candidate genes. To identify candidate genes from a functional perspective, I will then carry out a systematic transcriptional analysis of the cloned DNA sequences which include the bipolar I gene. These molecular genetic approaches should lead to a detailed characterization of the DNA segment which includes the bipolar I gene, thus providing a direct approach to critically evaluating potential candidates for the gene.